Endo-tropanamine is an important structural moiety of zatosetron maleate, a potent antagonist of the 5-hydroxytryptamine (5-HT.sub.3) receptor. The structure of zatosetron maleate is disclosed in U.S. Pat. No. 4,921,982 and others and is as shown below. ##STR1##
The endo-form of tropanamine is the preferred isomer for forming zatosetron maleate. In practice, zatosetron which has the exo-isomer of tropanamine is nearly inactive. As such, during the tropanamine synthesis it is necessary to remove as much of the exo-isomer as possible before reacting the tropanamine with the furan acid chloride intermediate to form zatosetron.
Unfortunately, existing methods of synthesizing tropanamine generate large quantities of the exo-isomer which must be separated prior to the zatosetron forming step of the process. In practice, the current methods of forming tropanamine result in the formation of between 10% and 20% of the exo-isomer which had to be removed by chromatographic and/or recrystallization procedures. This adds a step to the process and is costly and inefficient on a large scale basis.
Since it is desirable to simply carry the tropanamine forward to the zatosetron forming step (without further analysis or separation) a method had to be developed which would stereoselectively form a very high percentage of endo-tropanamine.
The previously accepted method of producing tropanamine-like compounds involved the catalytic hydrogenation of a Schiff base which was derived by reacting tropinone with benzylamine. While this procedure suggested that the equatorial face attack of the reagent would produce high stereoselectivity for the endo-isomer, in practice only an 8 to 1 or 9 to 1 ratio of endo/exo was formed, and poor yields were often the result (60%-70%). Since the overall yield was reduced even further by the separation step, it was highly desirous to discover a novel and more efficient synthesis for tropanamine and related compounds which gave high yields and was highly stereoselective.